An intra-tumor injection of a virus prevented further growth
of some pancreatic tumors and eradicated others in mouse models of pancreatic
ductal adenocarcinoma. However, some tumors continued growing despite this
treatment, proving resistant to the viruses. The research is published in the
March Journal of Virology.

About 95 percent of pancreatic cancers are pancreatic ductal
adenocarcinomas (PDAs). PDA is considered to be one of the most lethal
malignancies, resulting in a five year survival rate of only 8-20 percent.

In this study, the researchers, led by Valery Z.
Grdzelishvili of the University of North Carolina, Charlotte, tested several
species of virus against pancreatic tumors, most notably vesicular stomatitis
virus (VSV), a type of virus that is commonly used in the laboratory. Previous
studies had demonstrated that some other viruses, including adenoviruses,
herpesviruses, and reoviruses, could be used to kill pancreatic cancer cells in
some animal models of pancreatic cancer.

VSV has several qualities which make it attractive as a
potential oncolytic (cancer killing) agent. First, unlike some other viruses
(including adenoviruses),VSV replication does not require the cancer cell to
express a specific receptor in order to infect that cell, and therefore it can
infect most any cancer cell. Second, replication occurs in the cytoplasm of
host cells, which means that there is no risk that it will cause healthy host
cells to become cancerous, says Grdzelishvili. Third, this virus’s genome is
easily manipulated, which would make it fairly practical to adjust levels of
foreign gene expression to enhance the virus’ specificity for particular
cancers, and its ability to kill them. Fourth, unlike with some other viruses,
humans have no preexisting immunity to VSV.

In the study, the cancer-killing potential of several VSV
variants was tested against 13 clinically relevant cell lines of PDA, including
both primary PDA tumors and PDA metastases to the liver and lymph nodes, all
derived from human patients, and compared these to adenoviruses, Sendai virus,
and respiratory syncytial virus.

“In general, VSV variants showed superior oncolytic
abilities compared to other viruses, and some cell lines that exhibited
resistance to other viruses were successfully eradicated by VSV,” says
Grdzelishvili. “However, we found that PDA cells were surprisingly
heterogeneous in their susceptibility to virus-induced oncolysis and several
cell lines were resistant to all tested viruses.” In producing and responding
to interferon, many pancreatic cancers seemed to retain the normal antiviral
responses that normal, healthy cells have towards viruses, he says.

Grdzelishvili emphasizes that the VSV’s ability to kill
cancer cells in mouse models by no means guarantees that it would perform
similarly in cancer patients due to complex tumor microenvironments and
compromised immune responses. Most animal models involve simply inserting human
cancer cells underneath the animal’s skin, so that the cancers and their
environments are both quite different from cancer growing naturally in a human.

However, cancer cells that are resistant to virus in
laboratory dishes almost certainly would prove resistant in a human patient,
which means that such virus-resistant cancers could be identified with simple
laboratory tests prior to being applied to patients, says Grdzelishvili.

“Prescreening cells against an array of different viruses
could identify the best option for treating a particular tumor,” says
Grdzelishvili. Combined virotherapy (analogous to combination drug therapy)
could also potentially lead to enhanced cancer killing. “Understanding the
mechanisms and identifying biomarkers of resistance is critical for the
development of prescreening approaches and individualized oncolytic virotherapy
against PDA,” says Grdzelishvili.